Numerous clinical studies have established the debilitating side effects of cancer therapies on cognition, and the major impact that these cognitive impairments have on quality of life. For those patients afflicted with primary and metastatic brain tumors, radiotherapy remains the only tenable option for impeding disease progression. Approximately 200,000 patients/yr receive whole or partial-brain irradiation in the U.S., and half of these patients survive over 6 months. To date, there are still no satisfactory long-term treatments for reducing the progressive adverse late effects of radiation-induced brain injury. Pediatric cases are of particular concern, as children treated with cranial radiotherapy can lose up to 3 IQ points/yr and often live long lives post-cancer. Even low doses of cranial irradiation that elicit minimal morphologic injury can result in variable degrees of cognitive dysfunction that manifest as impaired learning, memory, attention, concentration, and executive function. Therefore, with the exception of survival, cognitive impairment resulting from the clinical management of cancer may well be the most critical criterion for evaluating therapeutic outcome and long-term quality of life. Recent advances in treatment mean that cancer patients are surviving longer, making long-term function and quality of life a major priority. The foregoing highlights the urgent need to develop effective long-term strategies for preventing cognitive decline. The present proposal is focused on developing an innovative stem cell transplantation strategy. In our previous studies, we found that transplanted human embryonic (hESC) and neural stem cells (hNSC) rescue radiation-induced cognitive impairment in rats, providing the first evidence that stem cell strategies can be used effectively to ameliorate radiation-induced normal-tissue damage in the brain. Based on these significant and novel findings, we propose a comprehensive series of studies to investigate the translational potential and mechanistic basis underlying the capability of intrahippocampal transplantation of hNSCs to restore cognition in cranially irradiated rats. We propose the following Specific Aims: 1) determine if the effectiveness of stem cell transplantation depends on dose or dose fractionation, 2) determine the optimal post-irradiation transplantation time for restoration of impaired cognition, 3) determine whether trophic support derived from transplanted stem cells provides a mechanism for rescuing radiation-induced cognitive deficits, and 4) determine whether functional integration of grafted stem cells provides a mechanistic basis for the rescue of radiation-induced cognitive dysfunction. Successful completion of these specific aims will allow us to evaluate the potential promise of using stem cells strategies in the clinic, and will elucidate the mechanisms underlying the beneficial effects of transplanted stem cells in ameliorating radiation-induced brain injury. PUBLIC HEALTH RELEVANCE: The debilitating cognitive side effects of cranial irradiation are well characterized, but to date, this highly problematic issue remains poorly understood. Approximately 200,000 patients/yr receive whole or partial-brain irradiation, and roughly half of these brain tumor patients survive over 6 months. In fact, many cancer patients are now living longer (especially children who can lose up to 3 IQ points/yr) with debilitating cognitive deficits, so it is becoming more and more pressing to devise ways to improve long-term cognitive function after the cessation of toxic cancer treatment regimes. While short-term strategies have provided some benefit for ameliorating cognitive impairment, there are still no satisfactory long-term treatments for reducing the progressive adverse late effects of radiation-induced brain injury. Thus, there is a strong rationale for undertaking the research proposed in efforts to evaluate a stem cell based strategy as a potential clinical intervention for reversing cognitive impairments and improving quality of life. Collectively, the proposed studies will provide baseline and mechanistic data for determining the potential clinical utility of hNSCs in the treatment of radiation-induced cognitive disorders, studies we believe to be of major significance to millions of cancer survivors in the U.S. and worldwide.